Macrophages can have profound effects on the progression of chronic kidney disease (CKD) by shaping the innate immune response. For example, pro-inflammatory M1 macrophages secrete tumor necrosis factor-? (TNF) and Interleukin-1 (IL-1), both of which can promulgate kidney injury and fibrosis. Through activation of type 1 angiotensin (AT1) receptors in the kidney, the renin angiotensin system (RAS) similarly plays a key role in progressive kidney damage culminating in renal fibrosis. However, in contrast to the pathogenic actions of renal AT1 receptors, our recent studies have shown that stimulation of AT1 receptors directly on macrophages suppresses their generation of M1 cytokines and thereby protects the kidney from progressive fibrosis. We further find that activating the AT1 receptor on macrophages enhances their expression of the transcription factor Krppel like factor 4 (KLF4). In other disease models, KLF4 blunts the M1 polarization of macrophages, limiting their secretion of TNF, and we find that global TNF-deficiency ameliorates hypertensive CKD induced by RAS activation. We therefore hypothesize that AT1 receptor activation on macrophages attenuates RAS-dependent kidney damage and fibrosis by enhancing KLF4-mediated suppression of TNF. To test this, we will first determine the role of macrophage KLF4 in kidney disease, assessing renal damage and fibrosis in mice lacking KLF4 only in macrophages and wild-type controls subjected to the chronic angiotensin II infusion (HTN) and unilateral ureteral obstruction (UUO) models of kidney injury and fibrosis. We predict that KLF4-deficiency in macrophages will exacerbate RAS-dependent CKD by exaggerating their generation of TNF. Therefore, as a next step we will assess the contribution of the enhanced TNF production in macrophages to RAS-dependent CKD by subjecting mice with macrophage- specific TNF deletion (TNF MKO) to our HTN and UUO models of RAS activation. Lastly, our hypothesis predicts that during treatment with a global AT1 receptor blocker (ARB), TNF induction accruing from AT1 receptor blockade on macrophages will diminish the renal protection afforded by blockade of renal AT1 receptors. To test this, we will compare HTN- and UUO-induced renal injury in TNF MKO and wild-type mice treated with an ARB and will determine if mice with macrophage-specific deletion of both TNF and the AT1 receptor have less kidney injury than those lacking the macrophage AT1 receptor alone. In the near term, these studies should guide strategies to use cytokine receptor blockade in conjunction with ARBs during progressive CKD. Over the longer term, distinguishing the contribution of AT1 receptors in the kidney to promote CKD progression from the protective effects of AT1 receptors on macrophages to mitigate M1- dependent tissue damage should facilitate the design of improved treatments for CKD.